The present invention relates to novel compounds having a platelet aggregation-inhibiting action, pharmaceutical compositions comprising the compounds as an active ingredient which can be used for inhibiting platelet aggregation, blood coagulation in extracorporeal circulation, the occlusion of arteries or reocclusion of coronary artery after PTCA and methods for inhibiting platelet aggregation, blood coagulation in extracorporeal circulation or the occlusion of coronary arteries.
Platelets play an important role in hemostasis by adhering to the surface of a damaged blood vessel. However, under diseased conditions, platelet aggregation is known to be primarily responsible for the formation of thrombi, which can obstruct blood vessels. This obstruction prevents the adequate supply of oxygen and nutrients to tissues and organs and thereby causes ischemic diseases in circulatory organs as represented by myocardial infarction and cerebral infarction. At present, the high mortality of these ischemic diseases has become a great social problem.
When medical treatments involving the extracorporeal circulation of blood, as exemplified by the use of artificial hearts and lungs during surgical operations and renal dialysis for patients with renal failure, are conducted, blood coagulation may be caused in the extracorporeal circulation of blood by the activation and aggregation of platelets, which is a great obstacle to the performance of such medical treatments.
It is suggested that platelet aggregation partakes in acute reocclusion after pericutaneous transluminal coronary angioplasty (PTCA) as applied to thrombi in coronary arteries in patients with cardiac infarction.
Hence, preventing thrombus formation, blood coagulation and reocclusion after the operation of coronary arteries by inhibiting platelet aggregation is very important for the purpose of preventing or treating ischemic diseases or performing medical treatments through extracorporeal circulation in a safe manner. It has become known in recent year that platelet aggregation also plays an important role in the progress of arterial sclerosis.
The process of platelet aggregation consists of two stages, i.e., the activation of platelets and a subsequent aggregation mediated by cross-linking protein "fibrinogen" in plasma. Almost all platelet aggregation-inhibiting agents heretofore in use target the first activation process. These agents include cyclooxygenase inhibitor aspirin, adenylate cyclase activator ticlopidine, phosphodiesterase inhibitor dipyridamole and the like. These compounds are not satisfactory in the specificity of action and the aggregation-inhibiting activity. Therefore, there is a need for the development of pharmaceutical agents having a more specific and potent action.
As regards the aggregation process mediated by fibrinogen, it is known that fibrinogen is associated with platelets by a very highly specific binding to glycoprotein "gpIIbIIIa" which is a fibrinogen receptor on the surface of platelet membranes. Inhibition of such platelet-specific binding will lead to the development of a highly specific drug. Inhibiting the binding of fibrinogen to platelets will also contribute to the creation of a potent and highly specific platelet aggregation-inhibiting agent because even activated platelets cannot aggregate if the fibrinogen-mediated aggregation process is inhibited.
In a study from the viewpoint of molecular biology, Andrieux et al. found that the binding of fibrinogen to a fibrinogen receptor is primarily dependent on an amino acid sequence in the fibrinogen molecule, that is, arginine-glycine-aspartic acid-phenylalanine (RGDF) (Andrieux et al., J. Biol. Chem., vol. 264, pp. 9258-9265, 1989).
An attempt was made to synthesize this partial peptide and its analogues and use them as fibrinogen receptor antagonists. Japanese Unexamined Patent Publication (hereinafter referred to as "KOKAI") Nos. Hei 1-190699 and Hei 2-62892, EPO 422937 A1 and U.S. Pat. (hereinafter referred to as "USP") No. 4,952,562 disclose tetrapeptide derivatives containing the RGD peptide. KOKAI No. Sho 63-215696 discloses derivatives consisting of peptides. KOKAI Nos. Hei 3-118331 and Hei 2-62892 and WO91/01331 disclose derivatives having the cyclic structure of the RGD peptide.
The RGD peptide is characterized in that it is digested in vivo by protease to amino acids which are safe and useful to the organism. Based on the finding of such a characteristic property, the inventors thought that for uses which did not require the sustained action of drugs, such as extracorporeal circulation and surgical operation, the creation of highly active peptide compounds having structures as similar to native peptides as possible was important for the development of platelet aggregation-inhibiting agents having few or no side effects. As a result of the various studies the inventors conducted, they developed novel peptides as described in KOKAI Nos. Hei 4-23864, Hei 5-203962, Hei 6-139107 and Hei 6-235745.
There are also reports on so-called peptidomimetics in which peptide structures containing more or less native amino acids were further derivatized and/or modified as described in KOKAI No. Hei 3-248808, WO93/16697, EP0503548, EP0502536, WO93/08181, WO93/08174, WO93/07867, WO94/08577, EP0445796 and EP0505868.
In general, compounds having chemical structures stable in vivo are required by drugs that need a sustained action. In the case of oral drugs, the stability and absorption of compounds in digestive tracts must also be taken into consideration. Peptides are generally unsuitable for such drugs of long lasting action because of their low stability.
EP445796 discloses acetic acid derivatives having .beta.-alanine residues which have a platelet thrombus formation-inhibiting action. The inventors have been developed independently acetic acid derivatives having a .beta.-alanine residue or mono-substituted .beta.-alanine residues, these compounds do not have a sufficiently high biological activity to be used for practical purposes and the development of compounds having a higher biological activity has therefore been desired.
An object of the present invention is to provide novel compounds that antagonize the action of fibrinogen receptors and which have a high platelet aggregation-inhibiting activity, in vivo stability and high bioavailability, as well as novel pharmaceutical compositions comprising the compounds as an active ingredient and therapeutic methods using the compounds.